The general objectives of the Program Project are: 1) to investigate the role of specialized membrane systems in the regulation of ion movements during excitation-contraction coupling in the heart; 2) to learn the mechanism by which membrane-bound receptors control transmembrane ion movements and intracellular enzyme activities to express their occupancy by agonists and antagonists; 3) to develop the use of a natural and synthetic class of compounds known as ionophores as tools for perturbing the ion gradients which control physiological processes in order to study the underlying control process and to explore the potentiality of ionophores as therapeutic agents for pathological conditions of the cardiovascular system, i.e., failure, shock, coronary insufficiency, etc. The approaches taken examine all processes from the presynaptic release of neurohumors, their postsynaptic recognition and conversion of the message into altered states of contractility. The level of experimental materials range from in vitro model systems, properties of subcellular units (isolated receptors, chromaffin granules, T-tubule vesicles, SR etc.) to whole tissues (heart, isolated arteries) and instrumented intact animals.